Rapid functionalization of multiple C-H bonds in unprotected alicyclic amines

The synthesis of valuable bioactive alicyclic amines containing variable substituents in multiple ring positions typically relies on multistep synthetic sequences that frequently require the introduction and subsequent removal of undesirable protecting groups. Although a vast number of studies have aimed to simplify access to such materials through the C-H bond functionalization of feedstock alicyclic amines, the simultaneous introduction of more than one substituent to unprotected amines has never been accomplished. Here we report an advance in C-H bond functionalization methodology that enables the introduction of up to three substituents in a single operation. Lithiated amines are first exposed to a ketone oxidant, generating transient imines that are subsequently converted to endocyclic 1-azaallyl anions, which can be processed further to furnish β-substituted, α,β-disubstituted, or α,β,α'-trisubstituted amines. This study highlights the unique utility of in situ-generated endocyclic 1-azaallyl anions, elusive intermediates in synthetic chemistry.